The dynamic control of FSH secretion during the normal menstrual cycle is critical to both follicular recruitment during the luteal-follicular transition and to its limitation in the midfollicular phase. In this Project we will determine the relative roles of estradiol and inhibin in this critical control of FSH secretion and will integrate both human and animal studies to probe the autocrine/paracrine control of FSH by activin/follistatin which cannot yet be fully approached in the human. SA#1 will address the overall hypothesis that inhibins A & B have distinct endocrine roles in the regulation of FSH secretion in women. The relationship of inhibins A & B to FSH will first be examined during the menstrual cycle in normal women. In experimental studies, the relative contributions of estradiol and inhibin to the negative feedback regulation of FSH secretion will be examined by blocking the estrogen receptor in women with GnRH deficiency in whom pituitary stimulation by GnRH can be controlled. From these studies, the role of inhibin can be inferred. SA#2 will examine the roles of activin and follistatin in the control of FSH biosynthesis and secretion during reproductive cycles in the female, combining 'in vivo' and 'in vitro' studies in the rat and human to begin to dissect the physiology of this autocrine/paracrine system. SA #3 will determine the relationship of inhibins A & B to FSH in the pathophysiology of infertility (older ovulatory women, infertile women with high FSH and PCOS) and their prognostic utility in ovulation induction and 'in vitro' fertilization (IVF). It is hypothesized that ovulatory cycles in both older women and infertile patients with elevated FSH levels will have low levels of inhibin, that abnormalities in inhibin will not explain the low FSH in patients with PCOS, and that inhibin A and/or B will represent improved predictors of outcome in ovulation induction and IVF cycles. While a thorough understanding of the dynamics of FSH regulation in normal women including the contributions of inhibins A & B, gonadal steroids, activin, and follistatin, is critical to understanding the pathophysiology of infertility in several key groups of patients, an even more important outcome of these studies will be the ultimate design of therapeutic options for patients with infertility that optimize conception while controlling the risks of multiple gestation.